Autosomal Dominant Inheritance
When an autosomal allele leads to a regular, clearly definable abnormality in the heterozygote, the trait is termed dominant. Autosomal dominant traits often represent defects in structural nonenzymatic proteins, such as in fibrillin in Marfan syndrome or collagen in Stickler syndrome. In addition, a dominant mode of inheritance has been observed for some malignant neoplastic syndromes, such as retinoblastoma, von Hippel–Lindau disease, tuberous sclerosis, and Gardner syndrome. Although the neoplasias in these diseases are inherited as autosomal dominant traits, the defect is recessive at the cellular level, with the tumors arising from loss of function of both alleles.
In dominant inheritance, the heterozygote is clinically affected, and a single mutant gene interferes with normal function. Occasionally, depending on the frequency of the abnormal gene in the population and the phenotype, 2 carriers of the same abnormality produce children. Any offspring of 2 heterozygous parents has a 25% risk of being an affected homozygote.
It has been suggested that dominant diseases are caused by mutations affecting structural proteins, such as cell receptor growth factors (eg, FGFR2 in Crouzon syndrome) or by functional deficits generated by abnormal polypeptide subunits (eg, unstable hemoglobins). The dominant disorders aniridia and Waardenburg syndrome result from loss of 1 of the 2 alleles for the developmental transcription factors PAX6 and PAX3, respectively.
Table 6-2 Characteristics of Autosomal Recessive Inheritance
Table 6-3 Characteristics of Autosomal Dominant Inheritance With Complete Penetrance
In some instances, dominantly inherited traits are not clinically expressed. In other instances—such as in some families with autosomal dominant RP—pedigree analysis can sometimes show a defective gene in individuals who do not manifest any discernible clinical or functional impairment. This situation is called incomplete penetrance or skipped generation.
Conclusive evidence of autosomal dominant inheritance with complete penetrance requires demonstration of the disease in at least 3 successive generations. Transmission of the disorder from a male to his male offspring, with both sexes showing the typical disease, must also occur. The characteristics of autosomal dominant inheritance with complete (100%) penetrance are summarized in Table 6-3. In the usual clinical situation, any offspring of an affected heterozygote with a dominant disorder, regardless of sex, has a 1 in 2 chance of inheriting the mutant gene and thereby demonstrating some effect. The degree of variability in the expression of certain traits is usually more pronounced in autosomal dominantly inherited disorders than in other types of genetic disorders. Moreover, when a clinical disorder is inherited in more than one mendelian pattern, the dominantly inherited disorder is, in general, clinically less severe than the recessively inherited one.
Counseling for recurrence risk of autosomal dominant traits must involve a thorough examination of not only the affected person (who may have the full syndrome) but also the parents. If 1 parent is even mildly affected, the risk of additional genetically affected siblings rises to 50%. It is crucial that ophthalmologists not miss variable expressivity when they have the opportunity to examine the parents of their patient and other family members. In some ocular disorders, family members can inherit a gene for a dominant trait and not show clinically apparent manifestations. In these cases, electrophysiologic testing or genetic testing can be used to detect the impairment. For example, a relatively inexpensive genetic test can show which clinically normal family members carry the mutation for Best vitelliform macular dystrophy.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.